A Unified Theory of Stress, Coagulation, Inflammation, Wound Healing, Embryological Development and Tissue Maintenance
Stress, n.: 1. —The reaction of the animal body to forces of a deleterious nature, infections and various abnormal states that tend to disturb its normal physiologic equilibrium (homeostasis). 2. —The resisting force set up in a body as a result of an externally applied force.(1)
Disorder is the basic law of the universe. Living creatures are ordered forms that employ combinations of information systems, chemical reactions, and mechanical mechanisms to acquire energy from their environment to maintain their structural integrity and function, and replicate. To be alive is to be unceasingly stressed by the demands of energy acquisition and structural maintenance.
Occam's Razor, a key concept in scientific philosophy, suggests that the best approach to a complex problem is to assume that the simplest explanation, or set of explanations, is correct until proven otherwise.
It has long been understood that humans and animals are equipped with physiological mechanisms that enable them to resist and repair the damaging effects of stressful stimulus, including coagulation, inflammation, scab formation, wound repair, and tissue maintenance. The observed reactions to stress are numerous, confusing and inter-related(2,3), and thus far no attempt has been made to describe a single mechanism that can explain these various phenomena. This manuscript will present a theory (“Stress Theory”) that endeavors to explain the biological reaction to stressful stimuli in terms of a simple, unified physiologic mechanism. The formulation of the theory was inspired by the author's observations of the clinical benefits of opioid-based anesthetic strategies, and has been greatly facilitated by recently published studies. It is intended to inspire new research that may lead to improved surgical outcome as well as general advance of medical understanding.
The Stress Theory may provide fresh insights to the nature of embryology, neonatology(4), physiology, immunology, pharmacology, and pathology. It may offer improved understanding of the mechanisms of drug actions, systemic vascular resistance, blood flow and distribution, blood pressure, atherosclerosis, thromboembolism, capillary homeostasis, apoptosis, embryological tissue development, muscle hypertrophy, athletic cardiovascular “conditioning”, blood coagulation, tissue inflammation, wound healing, Virchow's Triad, the “Fight or Flight” stress syndrome of Hans Seyle, Surgical stress, tissue remodeling and maintenance and numerous manifestations of pathology by describing all these in terms of the effects of a cohesive stress-opposing mechanism that operates continuously to maintain homeostasis and tissue integrity in the animal body(5).
Presently accepted coagulation “Cascade” theory provides an incomplete description of the coagulation process that defines coagulation Factors VII and VIII and thrombin as enzymatic proteins that react with one another and other blood-borne proteins to effect clot formation. Stress Theory is predicated on the alternate hypothesis that coagulation factors VII and VIII are blood-borne stress agents that respectively cause local and systemic elevations of thrombin levels and synergize each other's actions to produce hyper-elevations of thrombin at the site of stress (injury), and that thrombin is responsible for the numerous symptoms and effects exerted by the stress mechanism. Stress Theory offers a simpler and more complete explanation of hemostasis and coagulation than presently prevailing Cascade Theory, plus a simple explanation of wound healing, tissue maintenance, and important aspects of embryological development that is presently lacking.
Stress Theory assigns a role to Factor VII that might be compared to the “Extrinsic” cascade. It circulates in flowing blood and is separated from exposure to the underlying collagen that constitutes the major component of blood vessel structure by the vascular endothelium, which is only one cell layer in thickness. Disruption of the vascular endothelium therefore exposes factor VII to collagen, causing its activation. Its activity is normally localized and it focuses the effects of the Stress Mechanism at the site of injury (stress).
Likewise, the role of Factor VIII loosely corresponds to the “Intrinsic” cascade. It is a hormone that is produced and released directly into the blood by the vascular endothelium, a gland, under the control of the Sympathetic Nervous System (SNS), so that its blood level varies in accord with the tone and activity levels of the SNS. Its activity is systemic and its function is to regulate the activity level of the Stress Mechanism.
Both Factors VII and Factor VIII activate thrombin, and their combined effects cause localized hyper-elevations of thrombin that focus the effects of the stress mechanism at the site of stress and injury. The role of thrombin thus corresponds to the “Final Common Pathway” as described by Cascade Theory.
Stress Theory hypothesizes that thrombin is the primary enzymatic effecter agent of the stress mechanism. Thrombin is the known cause of numerous effects, including platelet activation(6), cell mitosis(7), cell hypertrophy, increased cell metabolism, inflammation(2), collagen production, and the conversion of fibrinogen to insoluble fibrin(8). It is closely associated with embryological development, wound healing, coagulation, malignancy, and tissue maintenance. Stress Theory hypothesizes Is that thrombin produces these multiple effects by means of a common mechanism that has yet to be identified.
Stress Theory postulates two mechanisms of hemostasis, both of which are controlled by blood levels of thrombin and “insoluble” fibrin. These are: 1. Capillary Hemostasis, which is initiated by closure of a molecular level Capillary Gate Mechanism governed by varying levels of “insoluble” fibrin and 2. Systemic Hemostasis, which is manifested by the familiar blood clot formation process that occurs in larger vessels. This is initiated by declines in blood turbulence and mixing that are initiated by increased blood levels of “insoluble” fibrin, a three-dimensional molecule with physical properties absent in its precursor, “soft” fibrin, and further enhanced by the formation of fibrin strands that connect various blood components to one another as turbulence and mixing decline.
The theory implies that changes in systemic vascular resistance occur in accord with the operation of the Capillary Gate mechanism and the degree of capillary hemostasis(9) as opposed to muscular contraction or relaxation of larger blood vessels. It asserts that the rapidly reversible physical properties of the three-dimensional matrix structure of insoluble fibrin, as controlled and facilitated by varying levels of Factor VIII, enable it to open and close the hypothesized Capillary Gate Mechanism to produce capillary hemostasis and indirectly regulate capillary perfusion. Simultaneously, insoluble fibrin increases systemic blood viscosity, which reduces blood turbulence and mixing, thereby increasing blood coagulability and thereby inducing clot formation. Hyper-elevations of insoluble fibrin in the immediate vicinity of stressful stimulus (injury), determined by the combined effects of Factors VII and VIII, reduce turbulence and mixing below a critical threshold, whereupon fibrin strands form inter-connections among blood components that further reduce turbulence and mixing, and clot formation proceeds to completion .
Chronic systemic elevations in blood viscosity, caused by persistent stressful stimulus and other factors cause reductions in blood turbulence and mixing that accelerate atherosclerosis in the arterial tree and increase the risk of thromboembolism in the venous system(10). Systemic vascular resistance and blood pressure(11) vary directly, and cardiac output and tissue perfusion vary inversely(12), with the degree of closure of the Capillary Gate mechanism as determined by the level of stress, SNS activation, and Factor VIII release.
Although thrombin plays an essential role in coagulation, most thrombin generation occurs after clot formation, suggesting that it may have additional functions(13,14). Stress Theory postulates that thrombin initiates coagulation and inflammation as a prelude to wound healing, and attracts various wound-healing cell types to the site of injury(15,16). It subsequently induces fibroblast mitosis, metabolism, proliferation and collagen production(17) as an integral part of the wound healing process. Thrombin levels continue to be elevated at the site of stress to regulate the wound-healing process in accord with continued collagen exposure to flowing blood, which maintains Factor VII activation. When wound healing is substantially complete, and collagen is sealed from exposure to flowing blood, thrombin levels fall. The decline in thrombin levels induces fibroblast apoptosis, signaling an end to the “active phase” of wound healing(18,19).
Maintenance levels of thrombin may stimulate collagen replenishment and tissue maintenance and remodeling, as evidenced by skin necrosis and ulceration and disturbances of wound repair(20) that sometimes result from treatment with coumadin, which exerts anti-thrombin effects(21-23).
Growing evidence suggests that the embryological development of complex multi-celled eukaryotic organisms may be largely governed by genetic programming contained in “junk” DNA in the form of “introns” that in the case of humans constitutes 95 percent or more of the genome(24). The introns may exert their effects on embryological development by controlling the timing of developmental processes, such as stem cell maintenance, cell proliferation, and apoptosis(25). Thrombin has been shown to be closely associated with cell maintenance(26), metabolism(27), hypertrophy(28-30), proliferation(31), angiogenesis(32) and apoptosis(19), and thrombin appears to play an important role in embryological development, as evidenced by fetal developmental defects that are associated with the administration of thrombin inhibitors to pregnant females and studies that demonstrate the role of thrombin in embryological development(31,33,34). I therefore hypothesize that introns control embryological development by controlling localized thrombin levels at precise time intervals. The stress mechanism, which also governs thrombin levels, may play a complimentary and synergistic role in embryological development by stimulating newly-developed organs and tissues to grow and enlarge in response to the stresses associated with fetal development. Assuming the presence of thrombin-sensitive growth and mitosis receptors common to all cells, the combined effects of introns and the stress mechanism to regulate thrombin levels may provide a simplified explanation of embryological development in complex organisms.
Nearly all forms of disease cause activation of the stress mechanism, typically manifested by a triad of 1. elevated blood levels of Factor VIII, 2. increased blood viscosity and 3. increased blood coagulability. These are often accompanied by a wide variety of seemingly unrelated pathological symptoms(35) due to inflammation, fibrin generation, and fibroblast proliferation. The stress mechanism may account for these symptoms. The Stress Mechanism is powerful, and may cause pathological effects, including malignancy, that are at odds with its healing function. Understanding the cause of these symptoms may offer insight into the nature of several hitherto mysterious stress-related diseases, such as rheumatoid disease(36), the tissue damage of diabetes, ARDS, asthma, inflammatory bowel disease(37-39), malignancy, eclampsia(40) and DIC. It may explain how stress-related conditions appear to exaggerate the incidence and severity of one another, as in diabetes and pregnancy, or in CREST syndrome(41). It may explain the fact that patients afflicted with one form of cancer are at increased risk of additional forms of cancer, how conditions that activate the stress mechanism may increase the risk of atherosclerosis and malignancy(42) and how environmental factors may increase the risk of stress-related disease(43,44). It may explain the associations between hypertension, systemic vascular resistance, blood viscosity(5), blood coagulability, atherosclerosis, and heart disease(45,46). It may suggest new forms of treatment and research. Finally, it may offer a logical way to employ anesthesia and surgical techniques to control stress and improve surgical outcome.